This invention relates to a non-milk based hypoallergenic infant-formula for xe2x80x9cat-riskxe2x80x9d infants no more than one year old, who have a documented milk allergy, such as cow""s milk allergy (xe2x80x9cCMAxe2x80x9d), and/or an allergy to protein in xe2x80x9csoy milkxe2x80x9d. By xe2x80x9cnon-milk basedxe2x80x9d is meant that no ingredient of the formula is derived from mammalian milk. Because typically, such infants have acquired digestive or absorption problems, the only source of protein in the formula is to be from free amino acids, and the formula is to be storable in powder form but have specified deliverability. By xe2x80x9cspecified deliverabilityxe2x80x9d is meant that the powder is solubilized in an essentially homogeneous liquid form within less than 30 secs when a unit dosage amount of 32.6 gm of the powder is manually shaken with water at 35xc2x0 C. in a bottle containing 240 ml (8 fl oz) of water. By xe2x80x9csolubilizedxe2x80x9d is meant that the powder is either soluble in water or forms an emulsion in water forming a liquid having physical characteristics analogous to those of human milk.
Still more particularly, the novel formula of the invention does not otherwise mimic human milk in that nutrient powder contains no intact or antigenic proteins; when the powder is solubilized as a ready-to-feed liquid, it is required to have a viscosity less than 10 cp at 25xc2x0 C. to allow flow through a tube if the formula is delivered enterally rather than taken orally. By xe2x80x9cintact proteinxe2x80x9d is meant a tripeptide or larger molecule having a molecular weight greater than about 500 Daltons; protein hydrolysates of whey or casein contain a major proportion by weight of tripeptides or larger molecules. Hereafter the term xe2x80x9centerallyxe2x80x9d specifically refers to feeding through a tube such as is typically inserted into the stomach of an infant who cannot easily be fed orally; and the term xe2x80x9cat-risk infantxe2x80x9d is used to specify one which is no more than one year old. The age limit is critical because a child more than one year old is not seriously xe2x80x9cat-riskxe2x80x9d since a one-year old is typically fed other food along with formula, and is relatively tolerant to an unbalanced formula for long enough a time to allow a competent nutritionist to alleviate the effects of the misdirected or misapplied diet. A typical infant, not a prematurely born infant, who is to be fed the novel formula weighs in the range from about 2.3 kg (5 lb) to 5.5 kg (12 lb) at birth, and weighs in the range from about 4.5 kg (10 lb) to 11.5 kg (25 lb) after one year.
The problem is to provide a storable powder formula which (i) provides the entire nutrition requirement of an at-risk infant needing an energy content in the range from about 200-250 Kcal/g nitrogen, without including any intact protein, (ii) is xe2x80x9cgut-healingxe2x80x9d, that is, effective to heal damage already inflicted on the infant""s digestive system, and (iii) yet meets the deliverability requirements specified. The problem is solved with a formula having a tailored distribution of amino acids and nucleotides which in combination with a source of unsaturated fats and relatively short chain carbohydrates and other ingredients, provide all the vitamin and mineral needs of the infant, yet prevent GI problems. A nucleotide consists of a nucleoside combined with phosphoric acid; a nucleoside is a compound made of a sugar and a purine or pyrimidine base, especially one obtained by hydrolysis of a nucleic acid, such as adenosine. The term xe2x80x9cnucleotidexe2x80x9d is used herein as an equivalent of xe2x80x9cnucleosidexe2x80x9d in that the form in which the compound is present is not critical so long as the specified number of xe2x80x9cnucleotide equivalentsxe2x80x9d are used. A xe2x80x9cnucleotide equivalentxe2x80x9d refers to the nucleotide content present in any one or more of the following forms: ribo-nucleosides, ribo-nucleotides, RNA, phosphate esters and d-ribose adducts of one with another; the various forms of nucleotides are determined, calculated and expressed as the monophosphate esters.
Unless there is reason to suspect an infant will be allergic to mammalian milk, such as cow""s milk, and/or to the protein in xe2x80x9csoy milkxe2x80x9d, as for instance when an older sibling suffered from the allergy, a typical infant acquires cow""s milk-induced enteropathy or enterocolitis, commonly referred to as xe2x80x9cdamaged gutxe2x80x9d, and becomes at-risk under several circumstances. The condition may be evident very soon if the infant is never breast-fed by its mother but is immediately fed an infant formula; the condition may be evident almost as quickly if the infant is breast-fed by its mother who drinks cow""s milk or goat""s milk; the condition may be evident a little later when the infant ceases to be breast-fed or the mother does not drink cow""s milk, or does not drink sufficient cow""s milk to impart evident signs of the condition in the infant; or the condition may be evident when the infant is breast-fed but not sufficiently well to provide all the infant""s nutrition. Such evident signs of xe2x80x9cdamaged gutxe2x80x9d include vomiting, diarrhea, and/or blood in the stool. A formula which fails to heal such damage is deemed deficient for the needs of an at-risk infant with damaged gut.
As will presently be evident, numerous infant-formulae purportedly especially formulated for infants and free of any milk-derived protein, fall far short of meeting the exigent requirements of a formula specifically directed to an infant in this particular mode of distress.
In particular, U.S. Pat. No. 5,719,133 teaches a dietary composition containing 100% free amino acids specially designed to provide a balance of amino acids for adolescents, but does not provide any nucleotides. Since the formula in the ""133 patent addressed a different problem, namely one where an adolescent needed the protein content essentially free of intact protein, but was otherwise unrestricted with respect to nutrients able to provide nucleotides, the amino acids provide from 10% to 20% of the total caloric content of the formula; the lipid component provides from 20% to 35% of the total caloric content with no restriction as to its source; and the carbohydrate provides from 50% to 65% of the total caloric content with no restriction as to the chain length thereof. However, it should not be surprising that the ranges of both essential and non-essential amino acids disclosed, and the ratios of certain amino acids to others, which ranges and ratios are designed to balance the diet of an adolescent, are inappropriate for an at-risk infant. It is found that the optimum lipid content for an at-risk infant-formula provides 50% of the total caloric content, but to solubilize fat in powder form for specified deliverability required adjusting the distribution of amino acids and nucleotides. Moreover, the carbohydrate content of the ""133 formula is too high, and the lipid content too low for a desirable formula for at-risk infants.
U.S. Pat. No. 5,066,500 to Gil et al teaches the use of any one or more of all nucleotides/nucleosides in a humanized milk formula for low-birth weight, premature and pre-term infants, teaches the use of cow""s milk sometimes as powder milk, and xe2x80x9cbutterfatxe2x80x9d in each example; and, for nitrogenous sources, teaches xe2x80x9ca mixture of dairy proteins (casein or sodium and calcium caseinates and lactose free lactalbumin) and protein hydrolyzates with low molecular weight (maximum molecular weight 1,000 Daltons, average molecular weight, 500 Daltons). As carbohydrate sources, glucose polymers are employed, such as dextrinmaltose with a different grade of dextrose equivalent degree, preferably between 10 and 30 DE. Fats are employed as a mixture of animal and one or more vegetable fats to meet the essential fatty acids requirements of patients.xe2x80x9d(see col 9, lines 45-55). There is no suggestion that the protein be provided by only a combination of essential and non-essential amino acids, and none that there may be anything critical about the choice of a spectrum of amino acids and nucleotides, each in specified ranges, which are chosen to be absorbed and utilized by an at-risk infant.
U.S. Pat. No. 4,544,559 to Gil et al teaches the use of any one or more of all nucleotides/nucleosides in a humanized milk formula for infants which formula is manufactured as a sterilized fluid or an instant powdered milk. Both fluid and powder purportedly contain nucleotides AMP, CMP, GMP, IMP and UMP at concentrations similar to those found in human milk, and the remaining components are said to comply with the standards of EPSGAN and AAP. However, the required precise ratios (sic) claimed are as follows: AMP (adenosine-mono-phosphate) 1.7 mg/L; CMP (cytidine-monophosphate) 1.5 mg/L; GMP (guanosine-monophosphate) 1.9 mg/L, UMP (uridine-monophosphate) 4.4 mg/L; and IMP (inosine-monophosphate) 0.6 mg/L. Though it is unclear whether the xe2x80x9cratiosxe2x80x9d are based on 1 L of humanized milk in liquid form, or whether the 1 L basis includes all the nucleotides added, it is clear that as in the ""500 patent, there is no suggestion that such a formula would meet the function of a complete nutritional support for an at-risk infant, or that specified ranges of nucleotides in combination with free L-Glutamine would allow damaged gut to heal and promote cell division for growth of the infant.
AU 200022638-A to Gil et al, assigned to Abbott Laboratories, discloses a nutritionally balanced nourishing product for preparation of infant formulas and dietetic products for adults which comprises adenosine and at least one other nucleoside. Whether fed to infants or adults, it is evidently essential that adenosine be present in combination with another nuecleoside irrespective of the remainder of the composition. But this is well known (see Gil et al European Patent No. 0302807 B1 , May 1988). Then Gil et al disclose a range of guanosine/guanosine phosphate is from 3.32-0.27 mg/l 100 g, dry basis, which is far less than the concentration required in the at-risk infant formula (10.97-5.1 mg/100 g, dry basis); and the disclosed range of cytidine/cytidine phosphate is from 10.16-3.52 mg/100 g, dry basis, which is far less than the concentration required in the at-risk infant formula (21.9-10.97 mg/100 g, dry basis). Since the only amino acid stated to be present in the Gil et al infant formula is L-cystine, carnitine being an amino acid derivative syntesized from lysine and methionine, it is evident that the Gil et al infant""s formula is not based on a combination of essential and non-essential amino acids. More importantly, Gil et al failed to recognize the importance of the concentration of free L-glutamine which should be in the range from 2-3 gm of free L-glutamine per 1000 cals.
Though one would be inclined to formulate an infant-formula in which each amino acid, whether xe2x80x9cessentialxe2x80x9d or xe2x80x9cnon-essentialxe2x80x9d, is present at the upper limit of the World Health Organization (WHO) and Life Sciences Research Office (LSRO) guidelines to ensure that the maximum amount of nutrition is delivered, such a formula is unlikely to meet the requirements of the Infant Formula Act (1980). It is noteworthy therefore that the relative amounts of nucleotides taught in the ""559 formulae are even less than the amounts specified for the lower ranges of the amounts found in human milk (see Table 1 below). Moreover, it is found that a formula with the relative amounts of nucleotides specified near the high end of the ranges in human milk would lack desired absorption and utilization by an at-risk infant, and also lack the specified deliverability. References teaching that each and every nucleotide may be used in a wide range of more than an order of magnitude (that is, the higher limit is more than 10 times greater than the lower limit) fail to enable one to choose the amount of a nucleotide which will be assimilated and utilized, do not suggest what the effect of high relative concentrations of particular nucleotides may be on the damaged gut of an at-risk infant, and provide no indication of the deliverability of a particular combination of amino acids and nucleotides irrespective of the other components of the infant-formula.
The inadequacy of the prior art resulted in having to choose not only the distribution of specific nucleotides but also that of individual essential and non-essential amino acids in the novel formula for an at-risk infant. The choice resulted in a different distribution compared to those used in the formula for a baby older than one year. In this regard it should be noted that xe2x80x9cessentialxe2x80x9d and xe2x80x9cnon-essentialxe2x80x9d amino acids are equally important in a healthy metabolic process, and the effect of omitting even a single amino acid from either category in an infant""s diet would result in failure of the infant""s body to use all other amino acids except as an energy source. Non-essential amino acids can be synthesized in the body, therefore need not be provided in the diet. Particularly because there are no WHO or LSRO guidelines for the distribution of non-essential amino acids, and the guideline for nucleotides is their concentration in human milk, much responsibility for an at-risk infant""s health is assumed when the distribution of amino acids, both essential and non-essential, is decided upon, though as a practical matter, a formula for an at-risk infant cannot be marketed for general use without the recipe falling within parameters set by both the WHO and LSRO.
Though each nucleotide may be used in a wide range found to be present in human milk, and it would be logical to use each nucleotide in an amount near the upper limit of its allowable range to ensure that the maximum amount of nucleotide is available to the infant, it has been found undesirable to do so. From the ranges of nucleotide equivalents present in human milk, set forth in Table 1 below, and the use in commercial infant-formulae of much lower amounts of each nucleotide than the allowable upper limit, it is evident that numerous considerations come to bear on a choice of the proportions in which the nucleotides are used relative to each other.
With respect to enriching an at-risk infant""s formula with nucleotides, there are currently available the following commercial brands: ENFAMIL infant formula, SIMILAC infant formula and private label infant formula manufactured by Wyeth (formerly known as SMA) but each is a milk-based formula unsuitable for an at-risk infant. In each of the marketed formulae is added a combination of particular vitamins, minerals, trace elements, etc., to supplement the diet provided by each infant-formula to satisfy as completely as possible, the needs of the infant, and avoid undue risk of undetected deficiencies.
It has been discovered that a non-milk based hypoallergenic infant-formula may be formulated to deliver no more than about 240 calories per 240 ml (8 fl oz) serving with about 50% of the calories derived from unsaturated fats and fatty acids, about 39% from carbohydrates, the remaining from free amino acids, it being essential that the formula is combined with nucleotides, essentially free of inosine, present in an amount in the range from 40 to 60 mg per liter of ready-to-feed infant formula, preferably about 76 mg of a specified distribution of nucleotides per 1000 calories of total caloric content, in combination with from 2-3 gm of free L-Glutamine per 1000 cals, so as to have a renal solute load of less than 200 mOsm/liter, all ingredients in a powder having a primary particle size such that more than 85% of the particles are smaller than 180 xcexcm, that is, pass through a No. 80 sieve, U.S. Standard Test Sieves (Wire Cloth), and which is deliverable as specified as a liquid having a viscosity less than 10 cp at 25xc2x0 C.
It is therefore a specific object of this invention to provide a non-milk based formula essentially free of protein hydrolysate, for an infant no more than one year old, afflicted with CMA and/or an allergy to the protein in xe2x80x9csoy milkxe2x80x9d, and/or digestive or absorption problems; the novel combination of key ingredients of the formula consists essentially of (i) a critically high amount of essential vegetable fats as triglycerides derived from relatively long C12 to C20 chain fatty acids, which fats have a caloric content in the range from 48-52%, most preferably 50%, of the total caloric content of the formula; (ii) relatively short chain length carbohydrates contributing less than 40% of total calories; and (iii) free amino acids including about 2-3 gm of free L-Glutamine/1000 cals, contributing the remainder of the caloric content; this level of glutamine is similar to the amount in human milk; the ability of an at-risk infant to utilize higher levels than 3 gm/l 1000 cals has not been extensively studied.
The novel dietary composition is required to be formulated as a powder with other ingredients adapted to provide storage stability and specified deliverability. Preferably the combined free amino acids provide from 10-12%, most preferably 11% of total calories, and the carbohydrate provides from 37-41%, most preferably 39% of total calories; the foregoing triglyceride-rich combination is then enriched with a chosen proportion of nucleotide equivalents for each nucleotide substantially to mimic the amounts present in human milk, preferably in the range from about 45-55 mg of combined nucleotides per liter. The proportions of amino acids and nucleotides in combination is chosen so as to provide a powder in which all amino acids and nucleotides are soluble and deliverable as specified.
It is another specific object of this invention to provide a palatable elemental formula having flavor desirable for an at-risk infant, and organoleptic properties and mothfeel patterned after human milk, provided osmolality at standard dilution (0.67 cal/ml), is maintained below 300 mOsm/Kg water, so as to effect in combination with the stated concentration of free L-Glutamine, healing of the infant""s damaged gut, and further provided the formula is enriched with a distribution of nucleotides essentially free of inosine, which formula is a nutritionally complete yet storable as a powder and deliverable as specified.
It is still another specific object of this invention to provide the above-described fats as relatively long chain triglycerides having in excess of 40 carbon atoms formed with fatty acids having in the range from C12 to C20 carbon atoms, which fats are unexpectedly highly assimilable by an infant in the absence of casein hydrolysate, yet the novel formula has specified deliverability because the combination of fatty acids used are easily solubilized without clumping so as not to clog the orifice in a nipple on a bottle.
A method is provided for nourishing an at-risk infant by feeding it with the above-described infant-formula which provides complete nutrition, promotes cell division for normal growth and allows the infant""s damaged gut to heal.